ESYT3

Summary

ESYT3 (extended synaptotagmin 3, HGNC:24295) is a protein-coding gene on chromosome 3q22.3, encoding Extended synaptotagmin-3 (A0FGR9). Binds glycerophospholipids in a barrel-like domain and may play a role in cellular lipid transport.

Predicted to enable calcium ion binding activity and phospholipid binding activity. Predicted to be involved in endoplasmic reticulum-plasma membrane tethering and lipid transport. Located in cytoplasmic side of plasma membrane; endoplasmic reticulum membrane; and endoplasmic reticulum-plasma membrane contact site.

Source: NCBI Gene 83850 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 150 total
• MANE Select transcript: NM_031913

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24295
Approved symbol	ESYT3
Name	extended synaptotagmin 3
Location	3q22.3
Locus type	gene with protein product
Status	Approved
Aliases	CHR3SYT
Ensembl gene	ENSG00000158220
Ensembl biotype	protein_coding
OMIM	616692
Entrez	83850

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000289135, ENST00000389567, ENST00000460133, ENST00000460325, ENST00000468103, ENST00000486831, ENST00000490835, ENST00000942986, ENST00000942987, ENST00000942988, ENST00000942989

RefSeq mRNA: 3 — MANE Select: NM_031913 NM_001322831, NM_001322834, NM_031913

CCDS: CCDS3101

Canonical transcript exons

ENST00000389567 — 23 exons

Exon	Start	End
ENSE00001837548	138434616	138435125
ENSE00002214646	138476818	138479925
ENSE00002223357	138472363	138472859
ENSE00003464892	138474221	138474352
ENSE00003470723	138470877	138471026
ENSE00003471867	138459187	138459253
ENSE00003473050	138473536	138473634
ENSE00003481783	138467561	138467609
ENSE00003518840	138460611	138460666
ENSE00003535317	138468105	138468194
ENSE00003537407	138452048	138452089
ENSE00003559097	138455194	138455328
ENSE00003562339	138476223	138476328
ENSE00003590572	138465339	138465421
ENSE00003592136	138476443	138476492
ENSE00003600242	138459945	138460034
ENSE00003614938	138457568	138457644
ENSE00003619169	138468819	138468881
ENSE00003619744	138468655	138468717
ENSE00003645800	138462086	138462206
ENSE00003647059	138470060	138470146
ENSE00003668476	138464345	138464515
ENSE00003683786	138469436	138469504

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 86.32.

FANTOM5 (CAGE): breadth broad, TPM avg 0.8439 / max 71.3125, expressed in 376 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38797	0.4358	235
38796	0.2606	134
38798	0.1476	68

Top tissues by expression

253 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	86.32	gold quality
upper lobe of left lung	UBERON:0008952	85.45	gold quality
right lung	UBERON:0002167	85.33	gold quality
cerebellar hemisphere	UBERON:0002245	85.32	gold quality
cerebellar cortex	UBERON:0002129	85.09	gold quality
right lobe of thyroid gland	UBERON:0001119	85.07	gold quality
skin of leg	UBERON:0001511	84.56	gold quality
upper lobe of lung	UBERON:0008948	84.44	gold quality
left lobe of thyroid gland	UBERON:0001120	84.13	gold quality
cerebellum	UBERON:0002037	83.63	gold quality
thyroid gland	UBERON:0002046	83.15	gold quality
skin of abdomen	UBERON:0001416	81.85	gold quality
zone of skin	UBERON:0000014	80.92	gold quality
secondary oocyte	CL:0000655	79.76	gold quality
sural nerve	UBERON:0015488	79.42	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.71	gold quality
lung	UBERON:0002048	78.69	gold quality
muscle layer of sigmoid colon	UBERON:0035805	78.39	gold quality
right uterine tube	UBERON:0001302	77.87	gold quality
right frontal lobe	UBERON:0002810	77.25	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.38	gold quality
body of uterus	UBERON:0009853	75.62	gold quality
calcaneal tendon	UBERON:0003701	75.42	gold quality
Brodmann (1909) area 9	UBERON:0013540	74.90	gold quality
adenohypophysis	UBERON:0002196	74.89	gold quality
pituitary gland	UBERON:0000007	73.83	gold quality
anterior cingulate cortex	UBERON:0009835	73.15	gold quality
smooth muscle tissue	UBERON:0001135	73.00	gold quality
cardiac muscle of right atrium	UBERON:0003379	72.89	gold quality
hypothalamus	UBERON:0001898	72.77	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	13.66
E-GEOD-124858	no	1.86

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

132 targeting ESYT3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690

Literature-anchored findings (GeneRIF, showing 5)

• two haplotype blocks of ESYT3 gene in 3q22.3 region that likely harbor functional variants and have a role in coronary artery disease in females (PMID:21733517)
• The extended synaptotagmins (E-Syt1, E-Syt2, and E-Syt3) are endoplasmic reticulum-anchored proteins. They form homo- and heteromeric complexes that mediate contacts with the plasma membrane. Such contacts are critically dependent on the presence of PI(4,5)P2 in this membrane and are additionally regulated by cytosolic Ca2+ via the Ca2+-sensing property of E-Syt1. (PMID:23791178)
• ESyt2 and ESyt3, but not ESyt1, interact with activated FGFR1. (PMID:25922075)
• Whole-exome sequencing reveals common and rare variants in immunologic and neurological genes implicated in achalasia. (PMID:34197731)
• Comprehensive analysis of the prognostic values and immune implication of ESYT3 in lung adenocarcinoma. (PMID:37657044)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	esyt3	ENSDARG00000006422
mus_musculus	Esyt3	ENSMUSG00000037681
rattus_norvegicus	Esyt3	ENSRNOG00000022704
drosophila_melanogaster	Esyt2	FBGN0266758

Paralogs (2): ESYT2 (ENSG00000117868), ESYT1 (ENSG00000139641)

Protein

Protein identifiers

Extended synaptotagmin-3 — A0FGR9 (reviewed: A0FGR9)

Alternative names: Chr3Syt

All UniProt accessions (2): A0FGR9, H7BXJ6

UniProt curated annotations — full annotation on UniProt →

Function. Binds glycerophospholipids in a barrel-like domain and may play a role in cellular lipid transport. Tethers the endoplasmic reticulum to the cell membrane and promotes the formation of appositions between the endoplasmic reticulum and the cell membrane.

Subunit / interactions. Interacts with ESYT1 and ESYT2.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane.

Tissue specificity. Widely expressed with high level in cerebellum and skin.

Domain organisation. Anchored to the endoplasmic reticulum membrane by a transmembrane hairpin structure; both N-terminus and C-terminus are cytoplasmic. The C2 domains mediate lipid and calcium binding. The N-terminal C2 domain binds calcium ions and is important for calcium-dependent lipid binding and interaction with membranes. Two calcium ions are bound at a high-affinity site and a third calcium ion is bound with lower affinity. May bind up to four calcium ions. In contrast, the second C2 domain apparently does not bind calcium. The third C2 domain mediates interaction with membranes enriched in phosphatidylinositol 4,5-bisphosphate and is required for location at the cell membrane. The SMP-LTD domain is a barrel-like domain that binds glycerophospholipids in its interior.

Similarity. Belongs to the extended synaptotagmin family.

Isoforms (2)

UniProt ID	Names	Canonical?
A0FGR9-1	1	yes
A0FGR9-2	2

RefSeq proteins (3): NP_001309760, NP_001309763, NP_114119* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR031468	SMP_LBD	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR037733	Ext_Synaptotagmin_C2A	Domain
IPR037749	Ext_Synaptotagmin_C2B	Domain
IPR037752	C2C_KIAA1228	Domain
IPR039010	Synaptotagmin_SMP	Domain
IPR051634	Extended_Synaptotagmin	Family

Pfam: PF00168, PF17047

UniProt features (33 total): binding site 13, sequence variant 4, domain 4, region of interest 3, topological domain 2, compositionally biased region 2, transmembrane region 2, splice variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A0FGR9-F1	71.92	0.23

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (13): 321; 322; 322; 332; 379; 379; 380; 381; 381; 381; 383; 385 …

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9845576	Glycosphingolipid transport

MSigDB gene sets: 105 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GCAAGGA_MIR502, GGGTGGRR_PAX4_03, GOBP_MEMBRANE_DOCKING, MARTINEZ_RB1_TARGETS_UP, TCCCCAC_MIR491, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, TGAGATT_MIR216, GOBP_ENDOPLASMIC_RETICULUM_ORGANIZATION, chr3q22, RASHI_RESPONSE_TO_IONIZING_RADIATION_5, GOBP_LIPID_LOCALIZATION, MARTINEZ_RB1_AND_TP53_TARGETS_UP, GOBP_ORGANELLE_LOCALIZATION, CAGCCTC_MIR4855P

GO Biological Process (2): lipid transport (GO:0006869), obsolete endoplasmic reticulum-plasma membrane tethering (GO:0061817)

GO Molecular Function (8): calcium ion binding (GO:0005509), calcium-dependent phospholipid binding (GO:0005544), phosphatidylethanolamine binding (GO:0008429), phosphatidylcholine binding (GO:0031210), phosphatidylinositol binding (GO:0035091), protein binding (GO:0005515), lipid binding (GO:0008289), metal ion binding (GO:0046872)

GO Cellular Component (7): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), cytoplasmic side of plasma membrane (GO:0009898), organelle membrane contact site (GO:0044232), endoplasmic reticulum-plasma membrane contact site (GO:0140268), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phospholipid binding	3
cation binding	2
binding	2
cellular anatomical structure	2
transport	1
lipid localization	1
metal ion binding	1
quaternary ammonium group binding	1
anion binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
plasma membrane	1
cytoplasmic side of membrane	1
organelle	1
organelle membrane contact site	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

620 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ESYT3	GRAMD2A	Q8IUY3	623
ESYT3	STIM1	Q13586	612
ESYT3	STIMATE	Q86TL2	581
ESYT3	OSBPL5	Q9H0X9	551
ESYT3	GRAMD1A	Q96CP6	540
ESYT3	ORAI1	Q96D31	534
ESYT3	SARAF	Q96BY9	532
ESYT3	PITPNM1	O00562	524
ESYT3	C22orf31	O95567	497
ESYT3	VAPA	Q9P0L0	481
ESYT3	BLOC1S4	Q9NUP1	464
ESYT3	C2CD2L	O14523	431
ESYT3	VAPB	O95292	423
ESYT3	OSBPL8	Q9BZF1	411
ESYT3	OSBP	P22059	403

IntAct

12 interactions, top by confidence:

A	B	Type	Score
ESYT3	ESYT2	psi-mi:“MI:0915”(physical association)	0.620
ESYT1	ESYT3	psi-mi:“MI:0915”(physical association)	0.620
ESYT3	ESYT1	psi-mi:“MI:0915”(physical association)	0.620
ESYT3	ESYT2	psi-mi:“MI:0403”(colocalization)	0.620
ESYT1	ESYT3	psi-mi:“MI:0403”(colocalization)	0.620
ESYT3	H2BC12L	psi-mi:“MI:0915”(physical association)	0.400
ESYT3	ESYT3	psi-mi:“MI:0915”(physical association)	0.400
SLC9A3	ESYT3	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): ESYT3 (Affinity Capture-MS), LOC102724334 (Proximity Label-MS), ESYT3 (Affinity Capture-MS), ESYT3 (Affinity Capture-MS), ESYT3 (Affinity Capture-MS), ESYT3 (Affinity Capture-MS)

ESM2 similar proteins: A0AVI2, A0FGR9, A3KGK3, A6NCM1, A6QQP7, B0DOB4, B3DLH6, B7FF09, B7ZC32, D3ZGS3, F1S5L4, O00329, O35904, O70145, O75923, P0DM40, P32019, P58069, P97564, Q0VA04, Q15283, Q17I16, Q1LXZ7, Q2WGJ9, Q32PH0, Q5DTI8, Q5GJ77, Q5RE88, Q5T0N1, Q5XIZ9, Q61586, Q62240, Q63713, Q69ZN7, Q6DCF6, Q6P5U7, Q6PA97, Q86VS3, Q86YR7, Q8BWR4

Diamond homologs: A0A075F932, A0FGR8, A0FGR9, A4IJ05, A6QP06, O00443, O00445, O00750, O08625, O08835, O35681, P04409, P05128, P05129, P10829, P21521, P21579, P21707, P24505, P24506, P24507, P29101, P34693, P40748, P40749, P41823, P46096, P46097, P47191, P47708, P47709, P47861, P48018, P50232, P59926, P63318, P63319, P70169, P70610, P70611

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

150 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	124
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4506 predictions. Top by Δscore:

Variant	Effect	Δscore
3:138455189:CACA:C	acceptor_loss	1.0000
3:138455191:CAG:C	acceptor_loss	1.0000
3:138455192:A:AG	acceptor_gain	1.0000
3:138455192:AGAT:A	acceptor_loss	1.0000
3:138455193:G:GA	acceptor_gain	1.0000
3:138455193:GAT:G	acceptor_gain	1.0000
3:138455193:GATC:G	acceptor_gain	1.0000
3:138455193:GATCA:G	acceptor_gain	1.0000
3:138455330:T:G	donor_loss	1.0000
3:138457566:A:AG	acceptor_gain	1.0000
3:138457567:G:GA	acceptor_gain	1.0000
3:138457567:GT:G	acceptor_gain	1.0000
3:138457567:GTGT:G	acceptor_gain	1.0000
3:138457567:GTGTC:G	acceptor_gain	1.0000
3:138457645:G:GG	donor_gain	1.0000
3:138459174:C:G	acceptor_gain	1.0000
3:138459249:TCCAG:T	donor_loss	1.0000
3:138459250:CCAGG:C	donor_loss	1.0000
3:138459251:CAGG:C	donor_loss	1.0000
3:138459252:AGGT:A	donor_loss	1.0000
3:138459253:GGTG:G	donor_loss	1.0000
3:138459254:GTGG:G	donor_loss	1.0000
3:138459255:T:A	donor_loss	1.0000
3:138459943:A:AG	acceptor_gain	1.0000
3:138459943:AGTT:A	acceptor_gain	1.0000
3:138459944:G:GG	acceptor_gain	1.0000
3:138459944:GTT:G	acceptor_gain	1.0000
3:138459944:GTTG:G	acceptor_gain	1.0000
3:138460031:GCCG:G	donor_gain	1.0000
3:138460667:G:GG	donor_gain	1.0000

AlphaMissense

5756 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:138464498:T:A	W357R	0.997
3:138464498:T:C	W357R	0.997
3:138474262:T:A	V793D	0.997
3:138455209:T:A	W129R	0.996
3:138455209:T:C	W129R	0.996
3:138470087:T:A	W511R	0.996
3:138470087:T:C	W511R	0.996
3:138464465:A:C	S346R	0.995
3:138464467:T:A	S346R	0.995
3:138464467:T:G	S346R	0.995
3:138464500:G:C	W357C	0.995
3:138464500:G:T	W357C	0.995
3:138469499:A:C	S500R	0.995
3:138469501:T:A	S500R	0.995
3:138469501:T:G	S500R	0.995
3:138435123:T:A	W109R	0.994
3:138435123:T:C	W109R	0.994
3:138452078:T:A	W120R	0.993
3:138452078:T:C	W120R	0.993
3:138459961:G:C	R222P	0.993
3:138465382:T:C	L377P	0.993
3:138457635:T:C	L191P	0.992
3:138465370:T:C	L373P	0.992
3:138468145:T:C	L420P	0.992
3:138460626:T:A	W252R	0.991
3:138460626:T:C	W252R	0.991
3:138464499:G:C	W357S	0.991
3:138476273:T:A	V840D	0.991
3:138469467:T:A	V489D	0.990
3:138464372:G:C	A315P	0.989

dbSNP variants (sampled 300 via entrez): RS1000012206 (3:138461925 T>C), RS1000079436 (3:138469031 C>A,T), RS1000160141 (3:138470295 G>A), RS1000172766 (3:138446386 G>A), RS1000391353 (3:138439434 C>T), RS1000408312 (3:138481089 G>T), RS1000443858 (3:138439272 C>A), RS1000448783 (3:138443428 A>G), RS1000645295 (3:138466387 C>T), RS1000695872 (3:138465932 G>A), RS1000726377 (3:138438116 C>T), RS1000777000 (3:138479466 A>G), RS1000777422 (3:138437842 A>G), RS1000861853 (3:138456691 T>A,C), RS1000891441 (3:138448819 T>C)

Disease associations

OMIM: gene MIM:616692 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007576_249	Chronotype	5.000000e-12
GCST012335_21	Hodgkin’s lymphoma	2.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
entinostat	increases expression, affects cotreatment	2
Valproic Acid	increases expression, increases methylation	2
bisphenol A	decreases methylation	1
terbufos	increases methylation	1
arsenite	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Fonofos	increases methylation	1
Estradiol	affects expression	1
Nickel	decreases expression	1
Parathion	increases methylation	1
Tobacco Smoke Pollution	affects expression	1
Urethane	increases expression	1
Vanadates	decreases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.